Viral suppression in the majority of HIV infected subjects can only be achieved with ART. Despite the significant decrease in inflammation and immune activation following ART, people under ART still exhibit low levels of both these activities leading to significant immune dysfunction that is illustrated by the inability to generae and maintain T cell and B cell immunity. Furthermore, ART therapy induces long and short-term toxicities leading to cardiovascular diseases and other complications. We have recently reported a significant dysfunction in the memory CD4 compartment in virally suppressed individuals undergoing ART. We have also shown a similar defect in the memory B cell compartment with these cells dying prematurely and producing significantly lower levels of anti-HIV antibodies when compared to natural controllers. Even when treated in the first few weeks after infection, only a small percentage of HIV infected subjects are able to contain viremia upon cessation of ART. Whereas, the large majority of HIV infected individuals exhibit resurgence of viremia demonstrating the inability of the immune system to contain viral replication in the absence of ART. This provides a strong rationale to develop novel immunotherapies that aim at augmenting anti-HIV immunity in chronically infected individuals in the absence of ART with the purpose of achieving a functional cure. Thus the inability to achieve a functional immune response against HIV upon treatment interruption in virally suppressed subjects is a major problem. Thus, for the majority of HIV infected individuals (more than 85%), the goal of acquiring anti-HIV immunity in the absence of ART is only possible with the augmentation of adaptive immune responses. In this proposal we will study the underlying mechanisms that could be responsible for their defective immune response in an effort of moving closer towards achieving a functional cure. We will further work under the educated assumption that enhancing the CD4+Tfh/B cell axis is critical for attaining improved anti-HIV immunity.